Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) can activate tyrosine kinase activity, and thus the reactions that lead to cellular proliferation. Both overexpression and increased activity of EGFR would cause uncontrolled cell division.
The epidermal growth factor receptor tyrosine kinase (EGFR-TK) was the earliest discovered protein tyrosine kinase. It is widely distributed in various human tissue cell membranes, and overexpresses in most of tumors (e.g. bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer). There is an adenosine triphosphate (ATP) binding site in EGFR intracellular region and EGFR inhibitors may competitively bind to the ATP binding site, and thereby inhibit EGFR phosphorylation and block the downstream signal transduction, and in turn inhibit the growth, differentiation and metastasis of tumor cells. Nowadays the targeted tumor therapy based on EGFR receptor as a target is one of active research areas in cancer treatments and has also achieved remarkable curative effect in clinical studies.
Patent WO2009/104027 discloses a series of thieno[2,3-d]pyrimidine derivatives possessing activity to inhibit tyrosine kinases; Patent WO2009/104026 discloses some thieno[2,3-d]pyrimidine derivatives possessing anticancer activity, which bear a phenylamino substituent at the 4-position. The above-mentioned documents are hereby incorporated herein by reference.
The present invention, being based on Patents WO2009/104027 and WO2009/104026, introduces isoxazole heterocycle into the nucleus of thieno[2,3-d]pyrimidine. A series of thieno[2,3-d]pyrimidine derivatives containing isoxazole heterocycles has been synthesized. Their activity to inhibit colon cancer cell lines (HCT-116) and human lung cancer cell lines (A549) in vitro has shown that the compounds possess stronger inhibitory activity to inhibit colon cancer cell lines (HCT-116) and human lung cancer cell lines (A549) at a concentration of 1×10−4 M. They can be used as candidate compounds or lead compounds of antitumor and anticancer medicants.